Pharmaco-EEG analysis of ligands varying in selectivity for [alpha]1 subunit-containing GABA.sub.A receptors during the active phase in rats

• Published in: Psychopharmacology 2023-12, Vol.240 (12), p.2561
• Main Authors: Reeves-Darby, Jaren A, Berro, Lais F, Platt, Donna M, Rüedi-Bettschen, Daniela, Shaffery, James P, Rowlett, James K
• Format: Article
• Language: English
• Subjects: Animal experimentation; Benzodiazepines; Complications and side effects; Electroencephalography; Evaluation; GABA; Patient outcomes; Properties
• ISSN: 0033-3158
• DOI: 10.1007/s00213-023-06450-3

Rationale Benzodiazepines are known to evoke changes in cortical electrophysiological activity that can be correlated with action at distinct [gamma]-aminobutyric acid type A (GABA.sub.A) receptor subtypes. Objectives We used electroencephalography (EEG) paired with electromyography (EMG) to evaluate the role of [alpha]1 subunit-containing GABA.sub.A receptors ([alpha]1GABA.sub.ARs) in benzodiazepine-induced sedation and changes in EEG band frequencies during the active phase of the light/dark cycle. Methods Male Sprague-Dawley rats (N = 4/drug) were surgically instrumented with EEG/EMG electrodes. The rats were injected i.p. with zolpidem, an [alpha]1GABA.sub.AR-preferring compound, or L-838,417, which has selective efficacy for [alpha]2/3/5 subunit-containing GABA.sub.ARs (i.e., [alpha]1GABA.sub.AR-sparing compound), in comparison with the non-selective benzodiazepine, triazolam. Results All ligands evaluated induced changes in sleep-wake states during the active phase consistent with an increase in slow-wave sleep (SWS). The degree of SWS increase appeared to be related to the magnitude of delta power band changes induced by the ligands, with the strongest effects engendered by the [alpha]1GABA.sub.AR-preferring drug zolpidem and the weakest effects by the [alpha]1GABA.sub.AR-sparing compound, L-838,417. Consistent with other research, a selective increase in beta band power was observed with L-838,417, which may be associated with [alpha]2GABA.sub.AR-mediated anxiolysis. Conclusions Overall, these findings support the establishment of pharmaco-EEG "signatures" for identifying subtype-selective GABA.sub.A modulators in vivo.